This project investigates a previously unknown function of the blood coagulation regulator Thrombomodulin and the natural protein C pathway in the hematopoietic stress response to radiation-injury and chemotherapy. We found that the endogenous Thbd- protein C pathway is required for the efficient recovery of hematopoiesis after lethal radiation exposure, and that pharmacologic supplementation of protein C pathway function prevents death caused by radiation-induced bone marrow failure. This proposal investigates the cellular and molecular mechanism mediating this newly discovered function of the Thrombomodulin-protein C pathway. Aim 1 identifies the as yet unknown relevant stromal and hematopoietic cell populations that express Thrombomodulin in normal bone marrow and in bone marrow exposed to myeloablative stress (radiation- injury and chemotherapy). Aim 2 tests the hypothesis that Thrombomodulin expression in stromal endothelium of the bone marrow is necessary for the normal recovery of hematopoiesis after myelosuppression; and that this effect of Thrombomodulin is based on its ability to augment in an EPCR- and PAR1-dependent manner the tie2- angiopoietin1-mediated recovery of the vascular stem cell niche. Aim 3 investigates the functional role of Thrombomodulin in hematopoietic stem and progenitor cells. This function is likely different from its role in endothelial cells and may involve the regulationof the supportive function of stromal macrophages in hematopoietic recovery from myelosuppression, as well as the cell-autonomous enhancement of myelopoiesis. Aim 4 delineates the contributions of aPC's anticoagulant and cell signaling functions to its therapeutic efficacy in supporting hematopoietic recovery from myeloablation. These studies will document a new physiologic connection between blood coagulation and hematopoiesis, and have the potential to significantly impact the current understanding of hematopoiesis and approaches to its pharmacologic manipulation.